Medications based on indole compounds derived from the Cruciferous family that includes cabbages, Brussels sprouts, cauliflower, and broccoli, and also synthetic analogues thereof are used extensively in medical practice today. Interest toward compounds in this group of compounds is explained, in particular, by their anti-carcinogenic and anti-estrogenic properties that make them suitable for treating diseases of the female reproductive system organs and certain hormone pathologies accompanied by hyperplastic processes. The most widespread diseases in this category include mastopathies, uterine myomas, endometriosis, adenomyosis, dysplasia of the uterine cervix of various etiologies, and hyperplasia of the thyroid.
Tumors of the reproductive organs are first in the structure of oncological morbidity among women, and morbidity increases by an average 1% a year. Tumors are second in the structure of mortality, and mortality “growth rates” (28%) remain the highest. According to WHO experts, about a million mammal cancer cases are registered around the world every year, a third of them with a lethal outcome. In the estimates of some researchers, five million women around the world will be suffering from this malignant tumor in the coming decade.
It is common knowledge that reproductive organ tissues are exposed continuously to the effect of a great variety of factors that stimulate active division (proliferation) and induce the start of specific signal cascades. These include three principal intracellular mechanisms that cause activation of cellular proliferation: (1) hormonal (or estrogen-dependent) mechanism; (2) mechanism induced by growth factors; and (3) mechanism activated by pro-inflammatory cytokines.
The involvement of estrogens in the development of neoplastic processes in hormone-dependent tissues (epithelium of mammary glands, endometria, and uterine cervix) is commonly recognized today and is viewed as one of the primary etiological factors for their development.
The pathogenetic mechanism of hyperplastic processes developing in the mammary gland have been studied well in our days. Obviously, by blocking the main signal transduction channels of signals stimulating proliferation of mammary gland cells, we can expect to be successful in preventing and treating pathological cases arising on this basis. In other words, pharmacological correction of hyper-proliferation diseases of reproductive system organs is to be undertaken at all stages and in respect of all signal cascades mediating key pathophysiological functions.
Many years of endeavors to find natural compounds blocking development of hyperplastic processes in hormone-dependent issues have, at last, resulted in success. Indole-3-carbinol (I3C) phytonutrient is one of these compounds that is contained in cruciferous vegetables (various kinds of cabbages). I3C provides protection against tumors owing to the broad spectrum of its biological activities. The clinical effect of I3C in various pathologies depends significantly on the individual specifics of the drug taking patients' metabolism, in particular, their ability to convert I3C to its various derivatives that, in turn, can interact synergistically and/or antagonistically (Dalessandri K. M., Firestone G. L., et al. (2004), Pilot Study: Effect of 3-Diindolylmethane Supplements on Urinary Hormone Metabolites in Postmenopausal Women with a History of Early-Stage Breast Cancer. Nutrition and Cancer, 50(2), 161-167).
3,3′-Diindolylmethane (DIM) is one of the derivatives produced by indole-3-carbinol upon oligomerization. This compound displays virtually all biological effects inherent in indole-3-carbinol, including its capacity to influence positively changes in the ratios of estrogen metabolites. DIM, however, is not transformed metabolically in the human organism and is a stable chemical compound. These distinctions of indole-3-carbinol from diindolylmethane make DIM a more preferable choice in pharmaceutical compositions with other pharmacologically active substances for treating hyperplastic and proliferative diseases.
DIM can be used to treat various inflammatory diseases (WO 2006105196, published on Oct. 5, 2006).
DIM has been found to induce proapoptotic death of cell with disturbed metabolism. In particular, DIM activates one of key apoptosis enzymes, Caspase-8, causing the death of transformed cells of intestinal cancer (Kim E. J., Park S. Y., et al. (2007), Activation of Caspase-8 Contributes to Diindolylmethane-Induced Apoptosis in Colon Cancer Cells, J of Nutrition, 137, 31-36). We assumed that the ability of DIM to activate apoptosis mechanisms can also extend to cells infected with intracellular microorganisms, in particular, Chlamydia Trachomatis. Chlamydial infection is very widespread and, in the view of many researchers, is one of the principal causes of female infertility. Antibiotics is a traditional therapy to treat chlamydial cervicitis. And yet, the infecting agent cannot be eradicated completely in almost 30% to 40% of the cases at the end of the treatment course, which causes the disease to recur. The reason is that the life cycle of Chlamydia Trachomatis consists of several stages, one of which, “inclusion bodies,” is resistant to antibiotics. This explains the insufficient efficiency of antibiotic therapy.
Researchers have been attempting to develop formulations having high diindolylmethane absorption.
In particular, a prior art pharmaceutical composition developed for treating mastopathy and endometriosis (U.S. Pat. No. 6,689,387 published on Feb. 10, 2004) consists of microparticles of I3C or 3,3′-diindolylmethane in a starch matrix, such as, for example, solid drug formulations for oral administration. These formulations contain 30% to 70% of starch that improves active agent solubility without giving them sufficient stability in storage.
DIM formulations on the basis of pegylated vitamin E are known in prior art (U.S. Pat. No. 6,416,793 published on Jul. 9, 2002). TPGS-based compositions, though, have helped achieve a very insignificant (not more than 50% to 100%) increase in biological availability of DIM, its analogues, and derivatives, for which reason the therapeutic potential of these compounds cannot be used to capacity. Besides, the preparation has to be spray-dried in a very power-intensive process that raises its production costs.
The closest prior art of the present invention described in international application WO 2009032699 (published on Mar. 12, 2009) relates to pharmaceutical compositions based on an anti-proliferative combination of DIM, polyunsaturated fatty acids (PUFAs), and folic acid. These compositions are disadvantageous because they are not stable enough, the principal component precipitating as tiny crystals in storage. Moreover, most people being short of omega-3 fatty acids, derived PUFAs may only have exaggerated effects. According to recent findings, addition of folic acid is undesirable for small children having inflammatory diseases of the autoimmune type.
Notably, indole derivatives have proved to be effective in pediatric practice. In particular, indole-3-carbinol and 3,3′-diindolylmethane are used extensively to treat respiratory papillomatosis of the larynx in young children (Auborn K. J. (2002), Therapy for Recurrent Respiratory Papillomatosis, Antiviral Therapy, 7(1), 1-9). Solid drug formulations are hard to divide into doses. Clinical practice requires liquid drug formulations that can be dosed accurately in 1 milligram per 1 kilogram of weight.